Convection enhanced delivery (CED) is a method of delivering drugs to the brain parenchyma using micro-catheters and controlled infusion rates to distribute drugs homogenously through the extracellular space, carried by bulk flow. This method may be used to deliver a wide range of therapeutics for neurological disease that can be targeted to specific brain areas, bypassing the blood brain barrier, and limiting side effects.
Drug distribution by CED is achieved by establishing a pressure gradient at the tip of the catheter that is sufficient to drive infusate through the extracellular space, in preference to it refluxing back along the catheter-tissue interface. To distribute therapeutic agents homogenously through large and clinically relevant volumes, the flow rate needs to be close to the maximum flow rate that the brain can safely tolerate. This is because the pressure gradient drops exponentially from the catheter tip and so to achieve bulk flow one has to establish a sufficient pressure gradient up to the boundary of the desired brain volume whilst competing against dynamic extracellular fluid clearance, particularly through the perivascular spaces, which act as peristaltic pumps. Excessive flow rates at the catheter tip will however result in tissue fracturing, and once this has occurred, the fracture will tend to be propagated in preference to distribution through the extracellular space. In addition, high flow rates are associated with increased reflux along the catheter-tissue interface, and the magnitude of this appears to be related to the extent of tissue trauma produced by catheter insertion and to the catheter's external diameter.
Significant adverse effects have been reported from clinical trials which are directly attributable to reflux of infusate into the subarachnoid space, including chemical meningitis, wound dehiscence and spinal root irritation. Therefore, it is desirable to reduce reflux of the infusate.
Reflux can be reduced when infusing into grey matter at flow rates of up to 5 μl/min, by using catheters that have an outside diameter of approximately 0.4 mm or less. When catheters of larger diameter are employed, they cause greater tissue trauma upon insertion in the annular space around them and through this low resistance pathway the infusate will reflux. However it has also been shown that if a catheter of larger diameter (0.6 mm) is left in situ for sufficient time to allow the tissue to heal, then it's tendency to reflux is substantially reduced.
It is also known that the tendency for a catheter to reflux can be reduced by a gradual ramp up of infusion rate, from a baseline infusion, for example 0.5 μl/min, stepwise over 20 minutes, up to 5 μl/min. It is thought that this gradual expansion of the interstitial spaces, under the influence of positive pressure and fluid content, increases the tissues fluid conductivity, whilst at the same time, the increased tissue pressure may act to improve the tissue seal along the tissue/catheter interface. It is of note that higher flow rates of infusion without reflux can be achieved in white matter than in grey matter (up to 10 μl/min) due to white matter's greater poroelasticity.
Minimising reflux may also be achieved by employing a cannula with a stepped outer diameter with the diameter of the step or steps decreasing from the proximal to the distal end (hereinafter referred to as a “stepped catheter”). The step may prevent or limit reflux along the catheter/tissue interface by focally compressing the tissue to create a seal. For the step to be efficient, the tissue sealing pressure achieved by tissue compression needs to exceed the hydraulic pressure from the refluxing fluid. The longer the length from the distal end of the catheter to the step, the greater will be the reduction in hydraulic pressure at the step. The tissue sealing pressure in the region of the step is likely to be proportional to the diameter change that creates the step. But this needs to be balanced against the tissue trauma that occurs in the region of the step when the cannula is inserted; because disruption of the cyto-architecture provides a low resistance pathway and greater fluid conductivity. An example of such a system is disclosed in WO2007/024841.